JPH1180176A - Production of sulfonic acid or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sulfide group-having phosphonic acid (salt) exhibiting an excellent anti-inflammatory action in high productivity in a state reduced in the production of by-products by hydrolyzing a sulfide group-having phosphonic acid ester in the coexistence of an alcohol. SOLUTION: This method for producing a sulfide group-having phosphonic acid (salt) comprises hydrolyzing a sulfide group-having phosphonic acid ester of the formula R is a 1-6C alkyl; X is a group of the formula: (CH2 )n [(n) is an integer of 1-3], 0, S: R1 is a 1-8C alkyl; Y is H, a 1-8C alkyl, a 6-12C aryl, a 1-6C alkoxy, a halogen} [e.g. 4-methylthiophenyl) thiomethanebisphosphonic acid tetraalkyl ester]. Therein, a 1-6C alcohol (e.g. methanol) is allowed to exist. Thereby, the amounts of by-products are reduced, and the objective sulfide group-having phosphonic acid (salt) e.g. [4-(methylthio) phenylthiolmethanebisphosphonic acid} exhibiting an excellent anti-inflammatory action is obtained in high productivity.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a sulfonium salt during the reaction in the presence of an alcohol when hydrolyzing a phosphonate ester having a sulfide group to produce a phosphonic acid having a sulfide group or a salt thereof. The present invention relates to the production of a phosphonic acid having a sulfide group or a salt thereof.

[0002]

2. Description of the Related Art Phosphonic acid having a sulfide group represented by (4-alkylthiophenyl) thiomethanebisphosphonate or a salt thereof (for example, Japanese Patent Publication No. Hei 8-26048)
Shows an excellent anti-inflammatory effect. This compound is synthesized by hydrolysis of a phosphonate having a sulfide group.

[0003]

In the hydrolysis reaction, the alkyl in the ester portion of the alkyl ester of (4-alkylthiophenyl) thiomethanebisphosphonic acid was replaced with the alkyl group of the alkylthio group at the 4-position of phenyl (4-alkylthiophenyl).
Alkylthiophenyl) thiomethanebisphosphonic acid [hereinafter referred to as S-alkyl form] For example, in the case of tetraisopropyl ester, the S-alkyl form is (4-isopropylthiophenyl) thiomethanebisphosphonic acid], which is produced as a major by-product (impurity). In order to reduce the amount of these impurities, it is necessary to lower the concentration of the acid used for hydrolysis and the concentration of the substrate, so that the reaction volume is about three times that of the previous reaction, and the productivity is increased. Was the biggest drawback.

[0004] The problem of the formation of by-products (impurities) can be solved if the alkyl of the alkylthio group and the alkyl of the alkyl phosphonate are the same alkyl. Cannot always be the same. For example, in the present invention, as the tetraalkyl methanediphosphonate, which is one of the raw materials, tetraisopropyl ester is preferable in terms of cost and availability on an industrial scale, and in the synthesis of a phosphonate alkyl ester having a sulfide group, In the case of tetraalkyl methanediphosphonate, the yield is low in the case of tetramethyl ester, and the yield is high in the case of tetraethyl and tetraisopropyl esters.

In order to solve the problem of suppressing the formation of by-products for the reasons described above, it is often impossible to make the same alkyl on a commercial scale.

An object of the present invention is to provide a novel hydrolysis method capable of producing the same amount of the desired compound in a smaller reaction volume than before without increasing the amount of the S-alkyl compound above the conventional level. That is.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that the alkyl group forming the sulfide group of the phosphonate ester during the hydrolysis reaction is reduced. Having alcohols having the same alkyl group coexist, intentionally forming dialkylsulfonium salts having the same alkyl group to protect sulfides, and having different alkyl groups that cause S-alkyl form formation It has been found that this problem can be solved by suppressing the production of dialkylsulfonium salts.

That is, the present invention provides a method for producing a sulfonium salt during the reaction in the presence of an alcohol when hydrolyzing a phosphonate ester having a sulfide group to produce a phosphonic acid having a sulfide group or a salt thereof. The present invention relates to the production of a phosphonic acid having a sulfide group or a salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, each component of the present invention will be described in detail.

In order to find a reaction condition satisfying the above requirements, when studying the hydrolysis reaction of an alkyl ester of (4-methylthiophenyl) thiomethanebisphosphonic acid, methanol was used as a cosolvent for hydrochloric acid as a reaction solvent. Then, it was found that a dimethylsulfonium salt was mixed in the phosphonic acid product. On the other hand, it was considered that the S-alkyl form was formed from the S-alkylmethylsulfonium salt. Therefore, when performing the hydrolysis reaction,
By coexisting methanol and intentionally generating a dimethylsulfonium salt, it has been discovered that the arylmethylsulfide can be protected and the formation of an S-alkylmethylsulfonium salt that causes the formation of an S-alkyl compound can be suppressed.

This reaction can be divided into a step of performing dimethylsulfonium salification at the same time as the hydrolysis reaction, and a step of decomposing the resulting dimethylsulfonium salt to lead to a target compound. The compounds targeted by the present invention and the reaction conditions are described below.

The phosphonate having a sulfide group used in the present invention is, for example, a compound having a bisphosphonic acid structure of the formula (1).

[0013]

Embedded image A is a phenyl group having at least an alkylthio group having 1 to 6 carbon atoms as a substituent. Examples of the alkylthio group having 1 to 6 carbon atoms include a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, hexylthio group and the like. The position of the alkylthio group on the phenyl group is not particularly limited, and may be any of the ortho, meta, and para positions. The number of alkylthio groups is at least one, and it does not prevent the presence of other substituents in the phenyl group.

X represents (CH ₂ ) n (where n represents an integer of 1 to 3), oxygen or sulfur, and examples of the alkylene group include methylene, ethylidene and propylidene. R ¹ is an alkyl group having 1 to 8 carbon atoms, for example, methyl,
Ethyl, propyl, isopropyl, butyl, pentyl,
Represents a hexyl group or the like. R ¹ is particularly preferably a methyl, ethyl, propyl or isopropyl group.

Among the compounds of the formula (1), a preferred compound as a phosphonate having a sulfide group is a bisphosphonate of the formula (2).

[0016]

Embedded image (Wherein, R represents an alkyl group having 1 to 6 carbon atoms, X and R ¹ are the same as defined above, Y is H, an alkyl group having 1 to 6 carbon atoms, and an aryl group having 6 to 12 carbon atoms. , Having 1 to 1 carbon atoms
6 represents an alkoxy group or halogen. That is, it is preferable that at least one alkylthio group (RS) on the phenyl group is in the para position. R has 1 or more carbon atoms
6 represents an alkyl group, and represents methyl, ethyl, propyl, ipropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl. Y represents H, alkyl, aryl, alkoxy, halogen, or the like; preferably, hydrogen or an alkyl group having 1 to 6 carbon atoms is an aryl group having 6 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, or butyl. Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Examples of the halogen include chlorine, fluorine, and bromine.

Among the compounds of formula (2), tetraalkyl 4-alkylthiophenylthiomethanebisphosphonate is preferably used. Preferred examples of these compounds include tetraethyl 4-methylthiophenylthiomethanebisphosphonate, tetrapropyl 4-methylthiophenylthiomethanebisphosphonate, tetraisopropyl 4-methylthiophenylthiomethanebisphosphonate, tetraethyl 4-ethylthiophenylthiomethanebisphosphonate. Methyl, tetrapropyl 4-ethylthiophenylthiomethanebisphosphonate, tetraisopropyl 4-ethylthiophenylthiomethanebisphosphonate, tetramethyl 4-propylthiophenylthiomethanebisphosphonate, tetraethyl 4-propylthiophenylthiomethanebisphosphonate, 4 Tetrapropyl propylthiophenylthiomethanebisphosphonate, tetramethyl 4-isopropylthiophenylthiomethanebisphosphonate,
Tetraethyl 4-isopropylthiophenylthiomethanebisphosphonate, tetrapropyl 4-isopropylthiophenylthiomethanebisphosphonate, and the like. Particularly preferred is tetraisopropyl 4-methylthiophenylthiomethanebisphosphonate.

The sulfonium salt formed at least in the present invention is a compound of the formula (3).

[0019]

Embedded image R is the same as the compound of the formula (2). The alkyl of the dialkylsulfonium salt may be different or the same, but the same is more preferable. R ² is identical carbon atoms and R ¹ 1
Represents up to 8 alkyl groups or hydrogen, or a pharmacologically acceptable cation, for example an alkali metal ion such as sodium, potassium, lithium, or an ammonium ion.

As the sulfonium salt formed in the present invention, 4-dimethylsulfonium phenylthiomethanebisphosphonic acid, 4-diethylsulfonium phenylthiomethanebisphosphonic acid, 4-dipropylsulfonium phenylthiomethanebisphosphonic acid, 4-diisopropylsulfonium phenylthione Methanebisphosphonic acid, 4-methylethylsulfonium phenylthiomethanebisphosphonic acid, 4-methylpropylsulfonium phenylthiomethanebisphosphonic acid, 4-methylisopropylsulfonium phenylthiomethanebisphosphonic acid, 4-ethylpropylsulfonium phenylthiomethanebisphosphonic acid, 4- Ethyl isopropylsulfonium phenylthiomethane bisphosphonic acid and the like. Particularly preferred are 4-dimethylsulfoniumphenylthiomethanebisphosphonic acid and 4-methylisopropylsulfoniumphenylthiomethanebisphosphonic acid.

Alcohol ROH used in the hydrolysis of the present invention
Is an alkyl group (R) described as the substituent RS group on the benzene ring of the phosphonic acid ester having a sulfide group, and has 1 to 6 carbon atoms. Preferred alcohols include methyl, ethyl, propyl alcohol and the like. In the present invention, the alcohol ROH coexisting to form a sulfonium salt is also preferably the same alcohol as described above.

The alcohol ROH used for or coexisted with the hydrolysis and / or the formation of the sulfonium salt is the same alcohol as the alkyl (R) of the substituent RS on the benzene ring of the phosphonate having a sulfide group.

In the present invention, a phosphonic acid having a sulfide group, which is a hydrolysis product, and a salt thereof are formed at least in part from a formed sulfonium salt. The concentration of hydrochloric acid used in the hydrolysis / sulfonium chloride reaction is preferably higher in order to reduce the amount of undesired S-alkyl compounds. It is preferably at least 6N, more preferably at least 10N, particularly preferably 12N (concentrated hydrochloric acid).

The reaction temperature of the hydrolysis / sulfonium chloride reaction is preferably from 80 to 130 ° C, more preferably from 90 ° C to 1 ° C.
It is 30 ° C, particularly preferably 90 to 120 ° C.

The amount of alcohol used is preferably 5% or more by volume with respect to concentrated hydrochloric acid (converted). More preferably 10% or more and 100% or less, particularly preferably 20 to 30%
%. However, in order to reduce the amount of alkyl chloride as a by-product, the amount of alcohol used is preferably as small as possible.

The preferred reaction time of the hydrolysis reaction / sulfonium chloride reaction is from 1 hour to 25 hours after the temperature of the reaction solution becomes constant. It is more preferably from 1 hour to 22 hours, particularly preferably from 1 to 20 hours.

In this hydrolysis reaction using a sulfonium salt, after the hydrolysis / sulfonium chloride reaction is completed,
It is necessary to decompose the sulfonium salt, and the conditions for efficiently decomposing the sulfonium salt are as follows.

In the hydrolysis / sulfonium chloride reaction step, it is preferable to carry out the reaction while refluxing the alcohol using a cooler, but in the sulfonium salt decomposition step, it is preferable to distill the alcohol from the system. . By this operation, the sulfonium salt can be efficiently reduced. That is, if the alcohol is not removed from the system, the sulfonium salt decomposition reaction will be slow and the reaction time will be long.

Accordingly, the reaction time depends on the efficiency of distilling off the alcohol, but the preferred reaction time is 3 to 30 hours, more preferably 7 to 25 hours. Prolonging the reaction time does not have any effect on the decomposition of the sulfonium salt, but is not preferred because it causes a problem in terms of productivity.

The reaction temperature for the decomposition of the sulfonium salt is desirably heated at a high temperature in order to effectively remove the alcohol, but is preferably 90 ° C. to 150 ° C., more preferably 100 ° C.
To 140 ° C.

Depending on the shape of the reaction vessel and the like, a small amount of alcohol condensed in the upper space (dead space) may remain without being completely distilled off, so that the amount of the sulfonium salt may stop at a certain level. For this reason, a device capable of efficiently distilling off is preferably used. Alternatively, in such a case, when the decrease of the sulfonium salt has stopped, the problem can be solved by filtering the reaction mixture, transferring the mixture to another reaction vessel, and then continuing heating.

By performing the above-described reactions and operations, the amount of the sulfonium salt can be reduced to a level that can be completely removed by a subsequent purification operation.

It is considered that the formation and decomposition of the sulfonium salt proceed simultaneously in the hydrolysis reaction system.

[0034]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 (Hydrolysis reaction 1) In a 300 ml three-necked flask, 40 g of tetraisopropyl (4-methylthiophenyl) thiomethanebisphosphonate was weighed, and a mechanical stirrer and a Dimroth were set. After purging with argon, methanol
Add 40 ml and stir. 160 ml of 12N hydrochloric acid is added, and the mixture is heated under reflux at a temperature of 90 ° C. for 7 hours. The Dimroth is replaced with a Claisen head, and the temperature is raised to 120 ° C. to remove low-boiling substances. Continue heating at 120 ° C. for 13 hours.

The reaction solution is filtered by allowing it to cool in a water bath. The filtrate
Put in a 300ml three-necked flask, mechanical stirrer,
Set the Claisen head and heat at 120 ° C. HPLC
The analysis is performed, and the heating is continued (it takes about 6 to 8 hours) until the sulfonium salt mainly composed of [4- (dimethylsulfonium) phenylthio] methanebisphosphonic acid becomes 0.5% or less.

After the completion of the reaction, the pH is adjusted to 3.5 to 4.6 by slowly dropping with a 40% aqueous solution of NaOH while maintaining the temperature at 50 ° C. or lower while cooling with water while stirring with a mechanical stirrer. After cooling for 1 hour with continued stirring, crystals are formed. The crystals are filtered, the filtrate is cut sufficiently, and the crystals are rinsed with ethanol.
Thereafter, when dried under reduced pressure at room temperature, crude crystals of disodium (4-methylthiophenyl) thiomethanebisphosphonate were obtained.
29.5 g were obtained. The content of (4-isopropylthiophenyl) thiomethanebisphosphonic acid in the crude crystals is 0.15% (HPL
C).

Example 2 (Hydrolysis reaction 2) In a 300 ml three-necked flask, 40 g of tetraisopropyl (4-methylthiophenyl) thiomethanebisphosphonate was weighed, and a mechanical stirrer and a Dimroth were set. After purging with argon, methanol
Add 40 ml and stir. Add 160ml of 12N hydrochloric acid and temperature 110 ℃
And heat to reflux for 20 hours. The Dimroth is exchanged for a Claisen head, and the temperature is raised to 120 ° C to remove low-boiling substances. [4-
Heating is continued (it takes about 6 to 8 hours) until the sulfonium salt mainly composed of (dimethylsulfonium) phenylthio] methanebisphosphonic acid becomes 0.5% or less (HPLC analysis).

After completion of the reaction, the reaction solution is allowed to cool in a water bath and filtered. Thereafter, while stirring the filtrate with a mechanical stirrer, a 40% aqueous NaOH solution is slowly added dropwise to keep the pH at 3.5 to 4.6 while maintaining the temperature at 50 ° C. or lower under water cooling. While continuing stirring
Crystals form on ice cooling for 1 hour. The crystals are filtered, the filtrate is cut sufficiently, and the crystals are rinsed with ethanol. Thereafter, when dried under reduced pressure at room temperature, 28.5 g of crude crystals of disodium (4-methylthiophenyl) thiomethanebisphosphonate were obtained.
Obtained. The content of (4-isopropylthiophenyl) thiomethanebisphosphonic acid in the crude crystals is 0.11% (HPLC)
Met.

Example 3 (Synthesis of sulfonium salt) (4-
40 g of tetraisopropyl (methylthiophenyl) thiomethanebisphosphonate was weighed out,
Set Jim Roth. After purging with argon, add 40 ml of methanol and stir. 160 ml of 12N hydrochloric acid is added, and the mixture is heated under reflux at a temperature of 90 ° C. for 7 hours. Then, hydrochloric acid is distilled off under reduced pressure using a water bath having a water temperature of 40 ° C. After the distillation is completed, the atmosphere is replaced with argon again, 40 ml of methanol and 160 ml of 12N hydrochloric acid are added, and the mixture is heated and refluxed at 90 ° C. for 3 hours while stirring.

After completion of the heating, hydrochloric acid is distilled off under reduced pressure using a water bath at a water temperature of 40 ° C. After completion of distillation, purging with argon is performed,
40 ml of methanol and 160 ml of 12N hydrochloric acid are added, and the mixture is heated and refluxed at 90 ° C. for 3 hours while stirring. After completion of the heating, hydrochloric acid is distilled off under reduced pressure using a water bath at a water temperature of 40 ° C. Thus, the sulfonium chloride reaction-hydrochloric acid distillation is repeated three times.

After the completion of the reaction, the product solution is poured into 500 ml of acetone to perform reprecipitation. The resulting crystals were recrystallized from water-ethanol to give [4-
20.7 g of (dimethylsulfonium) phenylthio] methanediphosphonic acid was obtained.

The proton nuclear magnetic resonance spectrum in heavy water is as follows. 1H NMR (D2O, 300MHz) 3.21 (s, 6H), 3.69 (t, 1H), 7.75 (d, 2H), 7.85 (d, 2H)
ppm

(Decomposition of dimethyl sulfonium salt) 300 ml
40 g of the obtained [4- (dimethylsulfonium) phenylthio] methanediphosphonic acid is weighed in a three-necked flask, and a magnetic stirrer and a Dimroth are set. After purging with argon, 200 ml of 12N hydrochloric acid is added, and the mixture is heated and refluxed at a temperature of 120 ° C. for 20 hours.

After the completion of the reaction, while stirring with a mechanical stirrer, the pH is adjusted to 3.5 to 4.6 by slowly dropping with a 40% NaOH aqueous solution while maintaining the temperature at 50 ° C. or less under water cooling. After cooling for 1 hour with continued stirring, crystals are formed. The crystals are filtered, the filtrate is cut sufficiently, and the crystals are rinsed with ethanol. Thereafter, drying under reduced pressure at room temperature gave 39 g of crude crystals of disodium (4-methylthiophenyl) thiomethanebisphosphonate.

Comparative Example (Hydrolysis reaction, in the absence of methanol) In a 300 ml three-necked flask, 40 g of tetraisopropyl (4-methylthiophenyl) thiomethanebisphosphonate was weighed, and a mechanical stirrer and a Dimroth were set. After purging with argon, 200 ml of 12N hydrochloric acid is added, and the mixture is heated at a temperature of 90 ° C. for 7 hours.

Exchange Jimroth for Claisen head,
The temperature is raised to 120 ° C to remove low-boiling substances. Continue heating at 120 ° C. for 13 hours.

The reaction solution is filtered by allowing it to cool in a water bath. The filtrate
Put in a 300ml three-necked flask, mechanical stirrer,
Set the Claisen head and continue heating at 120 ° C for 7 hours.

After the completion of the reaction, the pH is adjusted to 3.5 to 4.6 by slowly dropping with a 40% aqueous solution of NaOH while maintaining the temperature at 50 ° C. or less while cooling with water while stirring with a mechanical stirrer. After cooling for 1 hour with continued stirring, crystals are formed. The crystals are filtered, the filtrate is cut sufficiently, and the crystals are rinsed with ethanol.
Thereafter, when dried under reduced pressure at room temperature, crude crystals of disodium (4-methylthiophenyl) thiomethanebisphosphonate were obtained.
30.2 g was obtained. The content of (4-isopropylthiophenyl) thiomethanebisphosphonic acid in the crude crystals was 1.91% (HPL
C).

[0050]

Industrial Applicability According to the present invention, tetraisopropyl (4-methylthiophenyl) thiomethanebisphosphonate can be produced at approximately three times the production efficiency without increasing the amount of impurities [4- (isopropylthio) phenylthio] methanebisphosphonic acid. [4- (methylthio) phenylthio] methanebisphosphonic acid can be synthesized by hydrolysis of

Continued on the front page (72) Inventor Norio Kawabe 1111 Tehiro, Kamakura-shi, Kanagawa Prefecture Toray Industries, Inc. Basic Research Laboratory (72) Inventor Toshikazu Komagata 1111 Tehiro, Kamakura-shi, Kanagawa Prefecture, Toray Corporation Basic Research Institute

Claims (10)

[Claims] 1. A method for producing a phosphonic acid and a salt thereof, which comprises coexisting an alcohol when producing a phosphonic acid or a salt thereof having a sulfide group by hydrolyzing a phosphonic acid ester having a sulfide group. 2. The method for producing phosphonic acid and a salt thereof according to claim 1, wherein the alcohol coexisting is an alcohol having an alkyl group of the same kind as the alkyl group of the sulfide group. 3. The method for producing phosphonic acid or a salt thereof according to claim 1, wherein a sulfonium salt is formed during the hydrolysis. 4. The phosphonic acid ester having a sulfide group is a compound of the formula (1).
A method for producing the phosphonic acid or a salt thereof described above. Embedded image (Wherein, A represents a phenyl group having an alkylthio group having 1 to 6 carbon atoms as a substituent, and X is (CH ₂ ) n (where n is 1
Represents an integer of 1 to 3, oxygen, or sulfur, and R ¹ represents an alkyl group having 1 to 8 carbon atoms. ) 5. The method for producing phosphonic acid or a salt thereof according to claim 4, wherein the phosphonate having a sulfide group is a compound of the formula (2). Embedded image (Wherein, R represents an alkyl group having 1 to 6 carbon atoms, X and R ¹ are the same as defined above, Y is H, an alkyl group having 1 to 6 carbon atoms, and an aryl group having 6 to 12 carbon atoms. , Having 1 to 1 carbon atoms
6 represents an alkoxy group or halogen. ) 6. The method for producing phosphonic acid or a salt thereof according to claim 1, wherein the alcohol to be coexisted is an alcohol having 1 to 6 carbon atoms. 7. The phosphonic acid according to claim 1, wherein the phosphonic acid ester having a sulfide group is 4-RS-phenylthiomethanebisphosphonic acid tetraalkyl ester (R is the same as defined above). A method for producing the salt. 8. The method for producing phosphonic acid or a salt thereof according to claim 7, wherein the phosphonic acid ester having a sulfide group is a tetraalkyl (4-methylthiophenyl) thiomethanebisphosphonate. 9. The method for producing phosphonic acid or a salt thereof according to claim 1, wherein the sulfonium salt is a compound of the formula (3). Embedded image (Wherein, R and X are the same as defined above, and R ² represents an alkyl group having 1 to 8 carbon atoms, H or a pharmacologically acceptable cation.) 10. The method for producing phosphonic acid or a salt thereof according to claim 9, wherein the sulfonium salt is 4- (dimethylsulfonium) phenylthiomethanebisphosphonic acid and a salt thereof.